Cochrane · intervention · CD012744
Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy
Riley, P, Glenny, AM, Hua, F, et al. · Cochrane Database of Systematic Reviews · 2017 · Cochrane Library
Full textEvery question was extracted from the full review (methods and results), not only its Summary of Findings table.
Questions
111
current version
GRADE rated
17
No studies
20
Included studies
39
as reported
No studies 20 · 18%Ungraded 74 · 66.7%Very low 7 · 6.3%Low 9 · 8.1%Moderate 1 · 0.9%High 0 · 0%
Ungraded means an effect was reported without a GRADE rating; it is not a gap. No studies means the review found nothing to answer the question. The six categories are a display order, not a score.
Review question
| Element | Planned (methods) | Found (results) |
|---|---|---|
| Population | Participants of all ages, ethnic origin and gender scheduled to receive radiotherapy on its own or in addition to chemotherapy to the head and neck region; outpatients or inpatients | Adults scheduled to receive radiotherapy to the salivary glands for cancer (n=39 trials, 3520 randomised); majority male; head and neck cancer at various sites (n=36) or nasopharyngeal (n=3) |
| Intervention | Any pharmacological agent prescribed prophylactically for salivary gland dysfunction prior to or during radiotherapy, by any route, any dose and for any length of time (radiation techniques excluded) | Pilocarpine hydrochloride (n=12); Amifostine (n=12); Chinese medicine (n=5); Palifermin (n=3); Bethanechol (n=2); Biperiden plus pilocarpine (n=1); Artificial saliva (n=1); Selenium (n=1); Antiseptic mouthrinse (n=1); Antimicrobial lozenge (n=1); Polaprezinc (n=1); Azulene oral rinse (n=1); Venalot Depot / coumarin plus troxerutin (n=1) |
| Comparison | No preventative intervention; Placebo; An alternative pharmacological preventative measure | Placebo (n=21); No intervention (n=14); Head-to-head comparisons (n=4) |
| Outcomes | Primary: Xerostomia (subjective sensation of dryness); Salivary flow rates (stimulated or unstimulated). Secondary: Adverse effects; Survival data (overall, disease-free, progression-free, locoregional control); Other oral signs/symptoms; Quality of life; Patient satisfaction; Cost data | Xerostomia; Salivary flow rates (stimulated and unstimulated); Adverse effects; Overall survival; Progression-free survival; Disease-free survival; Locoregional tumour control; Quality of life; Other oral signs/symptoms (dysphagia, dysgeusia, oral pain, speech/eating difficulty); Cost data (n=1) |
| Study designs | Randomised controlled trials of parallel design | Randomised controlled trials of parallel design (n=39) |
| Timing | Data collected from the end of radiotherapy onwards (except for adverse effects) | Follow-up ranged from day 28 of radiotherapy to 34 months after radiotherapy |
Search date: 2016-09. Databases: Cochrane Oral Health's Trials Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE Ovid; Embase Ovid; CINAHL EBSCO; LILACS BIREME Virtual Health Library; Zetoc Conference Proceedings; OpenGrey; ClinicalTrials.gov; WHO International Clinical Trials Registry Platform
Questions and results
Pilocarpine vs No treatment/placebo
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Xerostomia (objective, LENT-SOMA scale) 6 months postRT | MD -0.40 [-0.69, -0.11] | 1 study · 39 participants | Ungraded |
Other oral related symptoms (oral discomfort, eating difficulty, mucosal pain, oral complications) End of RT | Insufficient evidence of a difference: oral discomfort MD -18.00 (95% CI -37.41 to 1.41); eating difficulties MD -14.40 (95% CI -35.38 to 6.58); mucosal pain MD -14.80 (95% CI -37.07 to 7.47); oral complications RR… | 2 studies | Ungraded |
Salivary flow rate (unstimulated) Up to and including 3 months postRT | MD -0.06 [-0.23, 0.11] | 1 study · 24 participants | Very low Downgraded: risk of bias, imprecision |
Xerostomia (dichotomous) End of RT; 3 months postRT | RR 1.00 [0.92, 1.08] | 2 studies · 48 participants | Ungraded |
Overall survival Up to and including 6 months postRT | RR 1.07 [0.80, 1.43] 724 per 1000 vs 775 per 1000 | 1 study · 60 participants | Very low Downgraded: risk of bias, imprecision |
Quality of life (McMaster HNRQ, 1-7 scale) Up to and including 6 months postRT | MD 0.20 [-0.19, 0.59] | 1 study · 90 participants | Very low Downgraded: risk of bias, imprecision |
Salivary flow rate (stimulated) Any time point | No evidence of a difference between treatment groups for stimulated salivary flow at any time point (Analysis 1.5) | 8 studies | Ungraded |
Adverse effects (other reported events) | No evidence of a difference for any other adverse event (nausea, vomiting, chilling, headache, lacrimation, dysphasia, weakness, nervousness, rhinitis, blurred vision, urinary frequency, dizziness, palpitation, skin… | NR | Ungraded |
Speech difficulties (VAS 0-100 mm) End of RT | MD 20.20 [1.93, 38.47] | 1 study · 34 participants | Ungraded |
Sweating (adverse effect) | RR 2.98 [1.43, 6.22] | 5 studies · 389 participants | Low Downgraded: risk of bias, imprecision |
Xerostomia (continuous, combined SMD) Up to and including 6 months postRT | SMD -0.35 [-1.04, 0.33] | 2 studies · 126 participants | Very low Downgraded: risk of bias, imprecision, inconsistency |
Biperiden plus pilocarpine vs No treatment
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Side effects | No data were reported on side effects. | 0 studies | No studies |
Survival | Survival not reported. | 0 studies | No studies |
Dysphagia (WHO grade 3+) 12 months postRT | RR 0.25 [0.03, 2.11] | 1 study · 60 participants | Ungraded |
Xerostomia | No xerostomia data related to the effectiveness of biperiden and pilocarpine were reported (Rode 1999). | 0 studies | No studies |
Salivary flow rate (unstimulated) End of RT | Insufficient evidence, from a single trial of 60 participants, to determine the effect on unstimulated salivary flow rate at the end of RT (Rode 1999; Analysis 2.1) | 1 study · 60 participants | Ungraded |
Amifostine vs No treatment/placebo
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Dysphagia (grade >= 3, 0-4 scale) End of RT; up to 3 months postRT | RR 0.50 [0.17, 1.48] | 2 studies · 73 participants | Ungraded |
Disease-free survival 24 months postRT | RR 0.94 [0.73, 1.21] | 1 study · 170 participants | Ungraded |
Dysgeusia (grade >= 2, 0-4 scale) End of RT | RR 0.24 [0.10, 0.61] | 1 study · 28 participants | Ungraded |
Vomiting (adverse effect) | RR 4.90 [2.87, 8.38] | 5 studies · 601 participants | Low Downgraded: risk of bias, imprecision |
Asthenia (adverse effect) | RR 2.91 [0.31, 27.24] | 1 study · 130 participants | Ungraded |
Salivary flow rate (mg/5 min, unstimulated) 12 months postRT | MD 0.32 [0.09, 0.55] | 1 study · 27 participants | Very low Downgraded: risk of bias, imprecision |
Cost (mean per-patient supportive care costs) End of RT | Mean per-patient supportive care costs lower with amifostine (USD 4401) than control (USD 5873); P = 0.02 (Buntzel 1998 / Bennett 2001) | 1 study · 28 participants | Ungraded |
Xerostomia (grade >= 2, 0-4 scale) Up to and including 3 months postRT | RR 0.66 [0.48, 0.92] | 5 studies · 687 participants | Low Downgraded: risk of bias, inconsistency |
Quality of life End of RT; up to 3 months postRT | MD 0.52 [-0.02, 1.06] | 1 study · 233 participants | Ungraded |
Xerostomia (grade >= 2, 0-4 scale) End of RT | RR 0.35 [0.19, 0.67] | 3 studies · 119 participants | Low Downgraded: risk of bias, inconsistency |
Allergic response (adverse effect) | RR 7.51 [1.40, 40.39] | 3 studies · 524 participants | Low Downgraded: risk of bias, imprecision |
Xerostomia (grade >= 2, 0-4 scale) 12 months postRT | RR 0.70 [0.40, 1.23] 418 per 1000 vs 292 per 1000 | 7 studies · 682 participants | Low Downgraded: risk of bias, inconsistency |
Salivary flow rate (unstimulated) End of RT | MD 0.34 [0.07, 0.61] | 83 participants | Ungraded |
Overall survival 12 to 24 months postRT | HR 1.18 [0.85, 1.66] 450 per 1000 vs 531 per 1000 | 2 studies · 271 participants | Very low Downgraded: risk of bias, imprecision |
Progression-free survival 12 to 24 months postRT | HR 0.94 [0.70, 1.27] | 2 studies · 247 participants | Ungraded |
Adverse effects (other reported events) | Alopecia, skin toxicity, hot flush, drowsiness, sneezing, hiccupping, dizziness and fatigue reported narratively or only for the amifostine group; insufficient evidence of a difference | NR | Ungraded |
Locoregional tumour control 12 to 24 months postRT | HR 0.90 [0.74, 1.11] | 2 studies · 279 participants | Ungraded |
Nausea (adverse effect) | RR 2.60 [1.81, 3.74] | 4 studies · 556 participants | Low Downgraded: risk of bias, imprecision |
Salivary flow rate (stimulated) End of RT to 12 months postRT | Insufficient evidence of a difference in stimulated salivary flow at any time point: end of RT MD -0.09 (95% CI -1.48 to 1.30); 3 months MD 0.38 (95% CI -1.43 to 2.19); 12 months MD 0.82 (95% CI -0.47 to 2.11);… | 2 studies | Ungraded |
Salivary flow rate (incidence of > 0.1 g saliva/5 min, unstimulated) 12 months postRT | RR 1.45 [1.13, 1.86] | 1 study · 175 participants | Ungraded |
Hypotension (adverse effect) | RR 9.20 [2.84, 29.83] | 3 studies · 376 participants | Low Downgraded: risk of bias, imprecision |
Quality of life (Patient Benefit Questionnaire, 10-point scale) 12 months postRT | MD 0.70 [0.20, 1.20] | 1 study · 180 participants | Very low Downgraded: risk of bias, imprecision |
Amifostine 200 mg/m2 three times weekly vs Amifostine 200 mg/m2 five times weekly
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Allergic response (adverse effect) | RR 1.00 [0.15, 6.64] | 1 study · 60 participants | Ungraded |
Survival (overall survival and locoregional control) | Insufficient evidence reported on overall survival or locoregional tumour control (Analysis 4.2; 4.3) | 1 study | Ungraded |
Nausea (adverse effect) | RR 0.64 [0.33, 1.25] | 1 study · 60 participants | Ungraded |
Salivary flow rate | No salivary flow rate data related to the effectiveness of different doses of amifostine were reported. | 0 studies | No studies |
Xerostomia (grade >= 2, 0-4 scale) 12 months postRT | RR 0.94 [0.58, 1.53] | 1 study · 49 participants | Ungraded |
Quality of life End of RT and 6, 12, 18, 24 months postRT | No significant differences between the three treatment arms (Jellema 2006) | 1 study | Ungraded |
Vomiting (adverse effect) | RR 0.25 [0.06, 1.08] | 1 study · 60 participants | Ungraded |
Amifostine (intravenous) vs Amifostine (subcutaneous)
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Quality of life | No data on either quality of life or other oral related symptoms were reported. | 0 studies | No studies |
Xerostomia (grade >= 2, 0-4 scale) 12 months postRT | RR 0.61 [0.42, 0.88] | 1 study · 127 participants | Ungraded |
Locoregional tumour control 48 months postRT | HR 1.34 [0.76, 2.36] | 1 study | Ungraded |
Salivary flow rate | No salivary flow rate data related to routes of administration of amifostine were reported. | 0 studies | No studies |
Adverse effects | Increased hypotension with intravenous delivery (20% vs 8%; P = 0.007); skin rash (10% vs 22%; P = 0.012) and local pain at injection site (0% vs 8%; P = 0.001) worse with subcutaneous; inconclusive for… | 1 study | Ungraded |
Overall survival 48 months postRT | HR 1.36 [0.89, 2.10] | 1 study | Ungraded |
Xerostomia (grade >= 2, 0-4 scale) Up to and including 3 months postRT | RR 1.03 [0.76, 1.40] | 1 study · 263 participants | Ungraded |
Chinese medicine vs No treatment/placebo
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Salivary flow rate (stimulated) End of RT | MD 0.09 [0.03, 0.15] | 1 study · 50 participants | Ungraded |
Side effects End of intervention; 1 month after RT | Insufficient evidence of a difference for any side effects | 2 studies | Ungraded |
Xerostomia (VAS) End of RT | Difference in favour of Chinese medicine on VAS xerostomia (P < 0.05); standard deviations not available (Wang 1998) | 1 study · 50 participants | Ungraded |
Quality of life End of intervention to 3 months postRT | Insufficient evidence to determine any effect on quality of life (Lin 2014; Analysis 6.5) | 1 study | Ungraded |
Overall survival 12 months postRT | Insufficient evidence to determine any effect on overall survival (Hu 2005; Analysis 6.4) | 1 study | Ungraded |
Xerostomia (dichotomous, Shenqi Fanghou recipe) End of RT | RR 0.39 [0.28, 0.55] | 1 study · 140 participants | Ungraded |
Xerostomia (other Chinese medicines) End of RT; 1 month after RT | No evidence of a difference for Tianwang Buxin Mini-pills (Lin 2014, 71 participants) or Jinlong capsules (Han 2010, 95 participants) | 2 studies | Ungraded |
Palifermin vs Placebo
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Progression-free survival 42 to 72 months from baseline | HR 1.06 [0.80, 1.42] | 3 studies | Ungraded |
Adverse effects | No evidence of a difference in reported adverse events across the three trials (nausea, fever, constipation, diarrhoea, headache, fatigue and others) | 3 studies | Ungraded |
Xerostomia (grade >= 2, 0-4 scale) Up to and including 3 months postRT | RR 0.97 [0.77, 1.22] 727 per 1000 vs 705 per 1000 | 3 studies · 471 participants | Low Downgraded: imprecision, inconsistency |
Salivary flow rate | None of the trials evaluating palifermin provided data on salivary flow rates. | 0 studies | No studies |
Overall survival 42 to 72 months from baseline | HR 1.00 [0.72, 1.39] 450 per 1000 vs 450 per 1000 | 3 studies | Moderate Downgraded: imprecision |
Dysphagia 3 months postRT | RR 1.32 [0.55, 3.13] | 3 studies | Ungraded |
Mouth and throat soreness (OMWQ-HN, 0-4 scale) 3 months postRT | MD -0.12 [-0.27, 0.02] | 2 studies | Ungraded |
Bethanechol vs Placebo
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Side effects | No statistical difference between groups in bethanechol-related toxicity; no patient experienced severe (grade 3) toxicity (Jaguar 2015) | 1 study | Ungraded |
Quality of life | No data on either quality of life or other oral related symptoms were reported. | 0 studies | No studies |
Salivary flow rate (stimulated, ml/min) 2 months postRT | MD 0.15 [-0.03, 0.33] | 1 study · 97 participants | Ungraded |
Salivary flow rate (unstimulated, ml/min) 2 months postRT | MD 0.19 [0.06, 0.32] | 1 study · 97 participants | Ungraded |
Survival | No survival data were reported. | 0 studies | No studies |
Xerostomia (grade >= 2, 0-3 scale) End of RT | RR 0.43 [0.28, 0.66] | 1 study · 84 participants | Ungraded |
Xerostomia (grade >= 2, 0-3 scale) Up to and including 3 months postRT | RR 0.81 [0.65, 1.01] | 1 study · 84 participants | Ungraded |
Bethanechol vs Artificial saliva
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Xerostomia (dry mouth, yes/no) 8 to 40 weeks postRT | RR 0.56 [0.30, 1.05] | 1 study · 30 participants | Ungraded |
Xerostomia (dry mouth, yes/no) End of RT | RR 0.63 [0.30, 1.29] | 1 study · 36 participants | Ungraded |
Overall survival 40 weeks postRT | RR 1.59 [0.43, 5.84] | 1 study · 43 participants | Ungraded |
Salivary flow rate (stimulated, ml/min) 8 to 40 weeks postRT | MD 0.21 [0.01, 0.41] | 1 study · 29 participants | Ungraded |
Salivary flow rate (unstimulated, ml/min) 8 to 40 weeks postRT | MD 0.07 [-0.02, 0.16] | 1 study · 33 participants | Ungraded |
Salivary flow rate (unstimulated, ml/min) End of RT | MD 0.12 [0.01, 0.23] | 1 study · 36 participants | Ungraded |
Salivary flow rate (stimulated, ml/min) End of RT | MD 0.13 [-0.03, 0.29] | 1 study · 32 participants | Ungraded |
Side effects | Low rates of adverse effects (watering eyes, nervousness, frequent urination, sweating, warm face, cramps, diarrhoea, nausea) with insufficient evidence of any differences (Jham 2007) | 1 study | Ungraded |
Quality of life | No data on either quality of life or other oral related symptoms were reported. | 0 studies | No studies |
Selenium vs No intervention
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Survival | No survival data were reported. | 0 studies | No studies |
Quality of life and other oral related symptoms (loss of taste, dysphagia) 6 weeks after end of RT | Insufficient evidence of differences for loss of taste or dysphagia; data largely unusable (no standard deviations). Ageusia milder in selenium group (not significant); dysphagia significant only at week 7 (P = 0.05)… | 1 study | Ungraded |
Xerostomia 6 weeks after end of RT | No evidence that selenium reduced xerostomia; data unusable (bar charts with no standard deviations) (Buntzel 2010) | 1 study | Ungraded |
Side effects 6 weeks after end of RT | 23 serious adverse events in the selenium group versus 22 in the control group (P = 0.476); no significant differences in toxicities (Buntzel 2010) | 1 study | Ungraded |
Salivary flow rate | No data on salivary flow rates were reported. | 0 studies | No studies |
Antiseptic mouthrinse vs Placebo
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Quality of life | No quality of life data were reported. | 0 studies | No studies |
Drooling (hyposialosis) 4 weeks from baseline | RR 1.43 [0.46, 4.39] | 1 study · 24 participants | Ungraded |
Salivary flow rate | Salivary flow rate was only reported during radiotherapy (i.e. not at any of the time points of interest); no usable data (Lanzos 2010) | 1 study | Ungraded |
Side effects | No relevant adverse events were reported in any group (Lanzos 2010) | 1 study | Ungraded |
Survival | No survival data were reported. | 0 studies | No studies |
Xerostomia | No data on xerostomia were reported. | 0 studies | No studies |
Antimicrobial lozenge vs Placebo
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Xerostomia Up to and including 3 months postRT | RR 1.16 [0.97, 1.40] | 1 study · 133 participants | Ungraded |
Survival | No survival data were reported. | 0 studies | No studies |
Nausea (adverse effect) Over 6 months | RR 1.90 [1.10, 3.28] | 1 study · 131 participants | Ungraded |
Quality of life and other oral related symptoms Over 6 months | Insufficient evidence of a difference for global quality of life, mouth pain RR 0.94 (95% CI 0.66 to 1.33), sore/burning mouth RR 0.95 (95% CI 0.68 to 1.35), throat pain RR 0.79 (95% CI 0.56 to 1.12) (Duncan 2005) | 1 study | Ungraded |
Side effects (other: dryness in mouth, diarrhoea, constipation) Over 6 months | Insufficient evidence of a difference: dryness in mouth RR 1.18 (95% CI 0.97 to 1.42), diarrhoea RR 1.97 (95% CI 0.51 to 7.54), constipation RR 0.91 (95% CI 0.59 to 1.42) (Duncan 2005) | 1 study | Ungraded |
Salivary flow rate | No data on salivary flow rates were reported. | 0 studies | No studies |
Polaprezinc vs Azulene oral rinse
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Side effects | No data on adverse events were reported. | 0 studies | No studies |
Survival | Tumour response by RECIST criteria reported for a specific group of patients only; no usable survival data (Watanabe 2010) | 1 study | Ungraded |
Taste disturbance (severe, > 2 on 0-3 scale) Over RT period | RR 0.12 [0.02, 0.83] | 1 study · 31 participants | Ungraded |
Salivary flow rate | No data on salivary flow rates were reported. | 0 studies | No studies |
Oral pain (severe, > 2 on 0-3 scale) Over RT period | RR 0.36 [0.17, 0.77] | 1 study · 31 participants | Ungraded |
Xerostomia (severe) End of RT | RR 0.17 [0.04, 0.65] | 1 study · 31 participants | Ungraded |
Disability of oral intake Over RT period | RR 0.31 [0.07, 1.31] | 1 study · 31 participants | Ungraded |
Venalot Depot (coumarin plus troxerutin) vs Placebo
Population: Patients receiving radiotherapy on its own or in addition to chemotherapy to the head and neck region
| Outcome | Effect | Evidence | Status / GRADE |
|---|---|---|---|
Survival (locoregional control) | Unable to use the data on locoregional control (Grotz 2001) | 1 study | Ungraded |
Quality of life | No data on either quality of life or other oral related symptoms were reported. | 0 studies | No studies |
Side effects | No adverse events could be attributed to the experimental medication (Grotz 2001) | 1 study | Ungraded |
Xerostomia | RTOG scores were a composite of radiation side effects on different sites and could not be used for assessing xerostomia (Grotz 2001) | 1 study | Ungraded |
Salivary flow rate | Sialometric data dropped to an unmeasurable level in both groups; abandoned as a marker of efficacy (Grotz 2001) | 1 study | Ungraded |